Photoredox-catalyzed diastereoselective dearomative prenylation and reverse-prenylation of electron-deficient indole derivatives

Prenylated and reverse-prenylated indolines are privileged scaffolds in numerous naturally occurring indole alkaloids with a broad spectrum of important biological properties. Development of straightforward and stereoselective methods to enable the synthesis of structurally diverse prenylated and reverse-prenylated indoline derivatives is highly desirable and challenging. In this context, the most direct approaches to achieve this goal generally rely on transition-metal-catalyzed dearomative allylic alkylation of electron-rich indoles. However, the electron-deficient indoles are much less explored, probably due to their diminished nucleophilicity. Herein, a photoredox-catalyzed tandem Giese radical addition/Ireland–Claisen rearrangement is disclosed. Diastereoselective dearomative prenylation and reverse-prenylation of electron-deficient indoles proceed smoothly under mild conditions. An array of tertiary α-silylamines as radical precursors is readily incorporated in 2,3-disubstituted indolines with high functional compatibility and excellent diastereoselectivity (>20:1 d.r.). The corresponding transformations of the secondary α-silylamines provide the biologically important lactam-fused indolines in one-pot synthesis. Subsequently, a plausible photoredox pathway is proposed based on control experiments. The preliminary bioactivity study reveals a potential anticancer property of these structurally appealing indolines.

1) The authors showed good substrate scope for amine precursors. However, only two examples have been shown for substituted indoles (3x, 3y). It is better to give more examples for substituted indoles.
2) Figure 6: The yield for product 12 should refer to the yield of the three steps.
Reviewer #2 (Remarks to the Author): The work "Photoredox-Catalysed Diastereoselective Dearomative Prenylation and Reverse-Prenylation of Electron-Deficient Indole Derivatives" by Feng, Liu and co-workers is a comprehensive study on the derivatization of electron-poor indoles. The strategy allows to obtain dearomatization and functionalization of two sites of the indole with high diastereoselectivity in a one-pot reaction.
The protecting group role was thoroughly investigated, and a tosyl substitution identified as the best to achieve high diastereoselectivity.
The mechanistic studies confirm a photoredox-catalyzed mechanism for the first reaction pathway, then followed by an Ireland-Claisen rearrangement. The radical attack on electron-poor indoles has received notable attention in the field of photoredox catalysis. Despite being overall a non-novel reaction pathway, the end product renders the work ingenious and of remarkable utility when considering possible further modifications, as demonstrated by the authors in Figure 6.
On contrary, the Ireland-Claisen rearrangement does not work with tertiary amine as a radical substrate. It would be interesting to see some other radical precursors viz. acids, boronic ester, or trifluoro borates as controls! Further, since the chosen radical precursors of choice were silanes, what about benzyl or alkyl ones?
The scope is also well-studied and broad. As indicated in the text, electron-poor indoles are required for the transformation. When considering substitution patterns on indoles, the authors only report two halogen substituted structures (3x and 3y). Are those the only tolerated substitutions? How do more electron-rich groups in those positions behave? Some additional references on radical indole difunctionalizations are missing (e.g. Nat Commun. 2020, 11, 3263, Org. Lett. 2022.
The SI is complete and reports full synthetic procedures and characterization of starting materials and final products.
Reviewer #3 (Remarks to the Author): The authors reported an interesting photoredox-catalysed tandem Giese radical addition/Ireland-Claisen rearrangement, providing an efficient method to achieve (reverse-)prenylation of electron-deficient indoles. The methods reported look to be effective to achieve the scaffolds described. The paper is certainly detailed, and a lot of work has been done. The paper is well written and presented, and the quality of the work looks to be high. My biggest concern is the novelty since the idea of dearomative prenylation of indole derivatives has been reported several times. And the advantages of this method are not obvious compared with previously reported methods. Therefore, the manuscript is not recommended to be published in Nature Communications. Detailed comments are as follows: 1. You and co-authors have realized the enantioselective dearomative prenylation of indole derivatives (nature catalysis, 2018, 1, 601), while this work only achieved the diastereoselective dearomative prenylation of indole derivatives.
2. Although the method uses photocatalysis, it is actually more cumbersome than the reported methods. The method is a two-step continuous reaction, but the second step needs to change the reaction conditions, and it need esterification and N-protection steps to readily prepare the radical acceptor.
3. The methods of Carreira, You and Stark have realized the construction of complex fusedheterocycle skeletons and even natural products, while this method is only suitable for the construction of indoline derivatives with simple structure.

The authors emphasizes "
Conventional approaches depend on the use of electron-rich indoles, this method achieved (reverse-)prenylation of electron-deficient indoles", in fact, the reaction process of this method requires the participation of carbonyl group on indoles, its reaction mechanism depends on the carbonyl group. This is also a limitation of the method because it is not applicable to the substrate without carbonyl group. Other methods have different reaction mechanisms, which do not mean that the dearomatization of electron-deficient indoles is difficult to achieve.
5. The antitumor activity of the synthesized indolines are too weak (IC50 > 5 μM) compared with reported kinase inhibitors (IC50 < 50 nM) for the human leukemia. The description of "compounds 3k and 3df displayed superior anticancer activity" is not appropriate.
In view of the above, this paper is not suitable for publication in Nature Communications. It is good work however, and publication elsewhere would be appropriate with minor changes. more examples for substituted indoles were investigated, including electron-rich and electron poor groups (5-Cl, 5-Br, 5-CN, 5-OMe, 5-Me, 6-OMe, 6-Me and 7-azaindole). The corresponding reverse-prenylated indolines were obtained in good yields with exclusive diastereoselectivity (46-73% yields, >20:1 d.r., 3x-3ae).
2. Figure 6: The yield for product 12 should refer to the yield of the three steps.
Response: We have revised the yield for product 12 for over 3 steps.
3. Figure 7a should be shown in higher resolution.
Response: Thanks for your kind suggestions. We have tried to improve the resolution in Figure 7a  Response: Thanks for your positive comments and kind suggestions. We investigated some other radical precursors to explore the structural diversity. It was found that the acid derivative (N-phenylglycine) underwent hydroalkylative dearomatization of indole 1d smoothly, however, the Ireland-Claisen rearrangement was completely suppressed (eq. a). On the basis of a related work by Glorius (Chem. Sci. 2021, 12, 2816-2822) using boronic esters as radical precursors, we conducted a similar experimental procedure with N-Ts indole 1d and cyclohexylboronic ester, affording the desired dearomative reverse-prenylation product in 32% yield over 3 steps (eq. b). When employing the benzyl trifluoro borate as a radical precursor, the desired dearomatizaiton/rearrangement product was not detected, but an unexpected desulfonylation of the N-Ts indole happened even in the presence of TMSCl (eq. c). Besides, we also attempted to evaluate the reaction of benzyl silane and N-Ts indole 1d. Under the standard conditions, there was no dearomatizaiton/rearrangement product.
Further optimization of the reaction conditions by varying photocatalysts and solvents was still failed to obtain the corresponding product, probably due to the high oxidation potential of benzyl silanes (eq. d). Response: Thanks for your kind suggestions. Reviewer 2 raised the same concern about the substitution patterns on indoles. To demonstrate the substrate scope, more examples for substituted indoles were investigated, including electron-rich and electron poor groups (5-Cl, 5-Br, 5-CN, 5-OMe, 5-Me, 6-OMe, 6-Me and 7-azaindole). The corresponding reverse-prenylated indolines were obtained in good yields with exclusive diastereoselectivity (46-73% yields, >20:1 d.r., 3x-3ae).
3. Some additional references on radical indole difunctionalizations are missing (e.g. Nat Commun. 2020, 11, 3263, Org. Lett. 2022. Response: Thanks for your comments. The You group have reported an enantioselective dearomative prenylation of indole derivatives via a palladium precursor and a chiral phosphoramidite-catalysed asymmetric allylic substitution reactions. It was an elegant methodology that focused on the dearomatization of electron-rich indoles via an ionic 2eactivation mode. Distinct from You's strategy, we show a photoredox-catalysed dearomatization of electron-deficient indoles via a radical 1eprocess. Both reaction mechanism and indole substrate scope, even prenylation and reverse-prenylation, are different from You and co-authors' report. In our view, this work is complementary to the known dearomative prenylation of electron-rich indoles. Therefore, it is not an overview assessment that emphasizes only diastereoselectivity versus enantioselectivity, while ignoring the objective differences between these two approaches. However, we can understand the reviewer's concern. Actually, the investigation of catalytic asymmetric version of dearomative prenylation of electron-deficient indoles via a visible-light photoredox catalysis is undergoing in our lab.
2. Although the method uses photocatalysis, it is actually more cumbersome than the reported methods. The method is a two-step continuous reaction, but the second step needs to change the reaction conditions, and it need esterification and N-protection steps to readily prepare the radical acceptor.
Response: In most cases, the dearomatizaiton/rearrangement process underwent spontaneously at the visible-light-activated stage, thus the second heating-step was not essential. To keep the conditions' uniformity and completely promote the rearrangement, we conducted the heating step after the first visble-light-irradiated step.
Actually, it is not a cumbersome or complex procedure, which only needs to turn off the light and heat at 60 o C for 3 hours or even without heating. As for esterification and N-protection, they are quite normal steps to prepare the substrates using the classical methods without any tedious or harsh conditions. For example, the reported methods via transition metals-catalysed allylic substitution reactions also required the conversion of allylic alcohol to its carbonate as an allyl electrophile reagent.
3. The methods of Carreira, You and Stark have realized the construction of complex fused-heterocycle skeletons and even natural products, while this method is only suitable for the construction of indoline derivatives with simple structure.
Response: Indeed, Carreira, You and Stark have realized the construction of complex fused-heterocycle skeletons and applied the corresponding approaches to natural product synthesis. Although the transition-metal catalysis (Ir, Pd, etc) with a two-electron transfer process is powerful in tuning the reactivity and selectivity, there are still some challenges in the tandem prenylation/cyclization process. For example, the prenylation/intermolecular dearomatiztion to achieve indole difunctionalizations was not involved in their research.
Herein, we introduced a conceptually distinct photoredox-catalysed radical strategy to prepare various prenylated and reverse-prenylated indoline derivatives. An array of structurally diverse amines including complex modified natural products and pharmaceuticals were employed as radical precursors, and were readily incorporated in indolines with high functional compatibility and isolated yields and excellent diastereoselectivity. We believe that these indoline derivatives are not simple structures, which are inaccessible or difficult to prepare with conventional approaches.
4. The authors emphasizes "Conventional approaches depend on the use of electron-rich indoles, this method achieved (reverse-)prenylation of electron-deficient indoles", in fact, the reaction process of this method requires the participation of carbonyl group on indoles, its reaction mechanism depends on the carbonyl group. This is also a limitation of the method because it is not applicable to the substrate without carbonyl group. Other methods have different reaction mechanisms, which do not mean that the dearomatization of electron-deficient indoles is difficult to achieve.
Response: In this manuscript, we never claim that the dearomatization of electron-deficient indoles is difficult to achieve. The present research status is that the available dearomatization reaction types of electron-deficient indoles are still limited in comparison with electron-rich indoles. One of the core processes in our strategy is the Ireland-Claisen rearrangement. As a classical named reaction, it provides a convenient approach to convert the carboxylic esters into the α-alkylated carboxylic acids. We have to admit that Ireland-Claisen rearrangement cannot be performed on substrates without a carbonyl group.
5. The antitumor activity of the synthesized indolines are too weak (IC50 > 5 μM) compared with reported kinase inhibitors (IC50 < 50 nM) for the human leukemia. The description of "compounds 3k and 3df displayed superior anticancer activity" is not appropriate.
Response: We agree with the reviewer's assessment that the description of "compounds 3k and 3df displayed superior anticancer activity" is not appropriate. In order to accurately describe the anticancer activity of compounds 3k and 3df, the "superior anticancer activity" was revised as the "potential anticancer activity".

REVIEWERS' COMMENTS
Reviewer #1 (Remarks to the Author): In this revision, the authors have explored more examples of substituted indoles and obtained good results. Other corresponding mistakes and comments have also been corrected or addressed. Therefore, it is suitable for publication on Nature Communication.
Reviewer #2 (Remarks to the Author): All of the reviewers' suggestions and comments have been effectively addressed in the amended version of the MS by Feng, Liu, and colleagues. I just noticed that the findings from the reviewing process were left out of the MS, which is fine, but these results would be helpful to the readers and would be worthy of a spot in the SI of this MS. I would accept this MS for publication in Nature Communication if that is taken care of.